The purpose of these studies is to define the pathogenesis of the disorders of esophageal motility such as incompetent lower esophageal sphincter (LES) and achalasia in order to develop rational drug treatment for these disorders. To do this, we will study the influence of parasympathetic, sympathetic and intramural neurons of the Auerbach's plexus on the basal sphincter pressure and sphincter relaxation and contraction. The role of gastrin in the genesis of the basal sphincter pressure and its role in modifying the sensitivity to excitatory agents such as a cholinomimetic agent will also be studied. These studies will be done in the opossum because in this species the lower part of the esophagus, like that in man, is composed of smooth muscle fibres. We have observed the electrical stimulation of the vagus nerves in the neck produces a frequency-dependent relaxation of the LES. Using this preparation, we will study the nature of the vagal inhibitory pathway, including the nature of the synaptic transmission between the vagal preganglionic neurons and the postganglionic inhibitory neurons. Interaction of sympathetic and parasympathetic activity will be studied by investigating the influence of adrenergic stimulation on the vagal- stimulated sphincter relaxation. These studies will be facilitated by local intra-arterial administration of various drugs. The contribution of the tonic neural activity in maintaining basal LES pressure will be estimated by antagonism of neural activity by tetrodotoxin and xylocain. This preparation will allow us to study the direct and indirect actions of various drugs on LES. We will also study the pathogenesis of LES suprasensitivity to cholinomimetic agents after bilateral cervical vagotomy and after intramural neuron block with tetrodotoxin and xylocaine.